An "autoimmune" disease is understood to be one where the target of the disease is "self" or "self antigen." There are a number of diseases that are believed to involve T cell immunity directed to self antigens, including (but not limited to) multiple sclerosis (MS), Type I diabetes, and rheumatoid arthritis (RA).
RA is a chronic inflammatory disorder characterized by joint pain. The course of the disease is variable, but can be both debilitating and mutilating. According to conservative estimates approximately 50,000,000 individuals are afflicted with RA worldwide. Those individuals are not only subjected to life-long disability and misery, but as current evidence suggests, their life expectancy is compromised as well. Unfortunately, despite considerable investigative efforts there is no cure for RA.
Established treatments of RA are designed to inhibit either final common pathways of inflammation or immunological mediators. Both approaches are non-specific and, therefore, are associated with severe side effects. Corticosteroids have multiple effects on the immune system and other tissues. Their use is complicated by very high incidence of musculoskeletal, metabolic, neurologic and connective tissue side effects, as well as immunosuppression which may lead to life-threatening infections. For this reason, corticosteroids are usually avoided until all other forms of treatment have failed. See generally, R. Million et al., "Long-Term Study of Management of Rheumatoid Arthritis," Lancet 1:812 (1984).
Cytotoxic and anti-metabolic drugs, such as methotrexate, azathioprine and cyclophosphamide are non-specifically affecting all rapidly dividing cells and therefore are associated with bone marrow and gastrointestinal toxicity and increased incidence of malignancy. In addition, methotrexate treatment of RA has been reported to induce liver damage and lung disease which may be fatal. See J. A. Engelbrecht et al., "Methotrexate Pneumonitis After Low-Dose Therapy for Rheumatoid Arthritis," Arthritis and Rheumatism 26:1275 (1983) and G. W. Cannon et al., "Acute Lung Disease Associated With Low-Dose Pulse Methotrexate Therapy In Patients With Rheumatoid Arthritis," Arthritis and Rheumatism 26:1269 (1983).
Most nonsteroidal anti-inflammatory drugs (NSAIDs) currently used are designed to non-specifically inhibit prostaglandin synthesis. NSAIDs currently in use modify or diminish--but do not arrest--the inflammatory response. Aspirin remains the most commonly used NSAID. Aspirin toxicity takes many forms, including hypersensitivity reactions, deafness, gastrointestinal and renal toxicity. See generally Simon and Mills, "Nonsteroidal Antiinflammatory Drugs," N. Eng. J. Med. 302:1179 (1980).
Gold compounds and penicillamine have also been used in the treatment of RA. They are both associated with high incidence of bone marrow, renal and mucocutaneous toxicity. Gold treatment, in particular, is associated with nephropathy. W. Katz et al., "Proteinuria in Gold-Treated Rheumatoid Arthritis," Ann. Int. Med. 101:176 (1984). Penicillamine, while questionably effective, is toxic even at relatively low doses. See W. F. Kean et al., "The Toxicity Pattern Of D-Penicillamine Therapy," Arthritis and Rheumatism 23:158 (1980). These problems have led to almost complete abandonment of these drugs in RA therapy.
Among the experimental therapies, cyclosporin and anti-TNF.alpha. antibodies show some promise. However, serious renal toxicity and non-specific immunosuppression limit significantly the utility of cyclosporin. Due to its ubiquitous role in many cellular functions, anti-TNF therapy may not be a safe therapeutic strategy for RA. While preliminary results indicate some promise with the anti-TNF approach, development of lupus-like disease has been noticed in some cases.
Thus, current therapies for RA are associated with high incidence of serious side effects. Furthermore, although some medications may offer symptomatic relief, in many cases, they do not significantly modify the progression of joint destruction. What is needed is an effective therapeutic approach with lower toxicity such that the treatment is better tolerated and more appropriate for the treatment of RA.